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Severe Congenital Neutropenia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
It is now clear that mutations in the genes encoding proteins involved in receptor binding (G-CSFR, CXCR4), endoplasmic reticulum (G6PT, G6PC3, JAGN1, VPS13B), ribosomes (SBDS), nucleus (GF11, GATA2), mitochondria (HAX1, TAZ, AK2), endosomes and lysosomes (AP3B1, LYST, RAB27A), and cytoskeleton (WAS, HAX1), increase endoplasmic reticulum stress and apoptosis, deregulate transcription factors expression, alter granulocyte colony-stimulating factor receptor (G-CSFR) signal transduction, leading to arrest of granulopoiesis and acquisition of second leukemia-associated mutation (e.g., RUNX1) before conversion to MDS and AML (Table 77.1) [3–11].
Advances in genetic and molecular understanding of Omenn syndrome - implications for the future
Published in Expert Opinion on Orphan Drugs, 2018
Whilst the relationship between Omenn syndrome and missense RAG mutations was clear, there were still some patients for whom a genetic diagnosis was unresolved. One report described five infants with Omenn syndrome, from four unrelated families, only two of whom had mutations in RAG1 [55]. Three other patients with similar clinical phenotypes had RAG gene polymorphisms, predicted not to affect endonuclease function. This suggested that mutations in other genes may mimic the Omenn syndrome clinical phenotype. A further report investigated seven cases of Omenn syndrome with appropriate clinic-immunophenotype in whom no defect in RAG genes had been found. All patients demonstrated absent TCRVB families; six had predominant TCRVB families, six had oligoclonal TCR gene rearrangements including TCRGD rearrangements [56]. The clinical phenotype has now been described in other VDJ recombination defects, including patients with mutations in DCLRE1C leading to Artemis deficiency [57], and in LIG4, which codes for DNA ligase 4 [58]. To date, patients with Omenn syndrome have now been described in most genetic forms of SCID including IL2Rγ deficiency, IL7Rα deficiency, adenosine deaminase deficiency, AK2 deficiency, haploinsufficiency of 22q11 causing DiGeorge syndrome, haploinsufficiency of CHD7 causing CHARGE syndrome, and defects in RMRP associated with cartilage hair hypoplasia [59–67]. However, the most commonly identified genetic defects are in the RAG1 and RAG2 genes.
Bioactivity and mechanisms of flavonoids in decreasing insulin resistance
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Min Zhou, William H. Konigsberg, Canhua Hao, Yinbo Pan, Jie Sun, Xiaojing Wang
This review has focussed on the mechanism by which flavonoids decrease IR and describes the biological activities of various flavonoids. We found that hydroxyl substitution at the 5 or 7 position of the A ring and at the 3′-5′ position of the B ring in the flavonoid skeleton played a beneficial role in reducing IR of the compounds. This is of great help to pharmaceutical work, and researchers can use it as a reference in design of drugs. Due to their wide range of activities, flavonoids have great potential in clinical application and clinical development, providing a basis for researchers and clinical workers. Although flavonoid compounds have shown powerful effects in vitro and animal experiments, such as decreasing IR, reducing blood glucose, and cardiovascular protection, in vivo experiments and clinical trials are lacking, so researchers still need to make further efforts. Few medications are currently being used to treat IR, but there is one drug in clinical phase I (Kareus Therapeutics’ KU-5039 targets AK2, PRKAB1, AK4 and AK1 to treat IR) and one drug in clinical phase II (Xortx Therapeutics’ Oxy- pure). The stage of clinical research by National Centre For complementa on Hesperetin to decrease IR is unknown, but the rich activity of flavonoids provides it with great potential. Although many of these compounds have not yet entered the clinic, the chemical synthesis and optimisation of flavonoids and their further derivatives are necessary in order to decrease IR and treat diabetes and metabolism-related diseases more effectively in the future. In addition, this class of compounds ameliorates the target of IR, providing great value for the design and development of more effective compounds to support human health.
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
Moreover, a mutation in the adenylate kinase 2 (AK2) gene causes reticular dysgenesis (RD) disease. This disorder is characterized by a significant decrease in the number and function of T- cells. AK2 deficiency leads to an impaired mitochondrial energy metabolism and lymphocyte differentiation and its maturation, but without effect on megakaryocytic maturation [67, 68]. Nonetheless, thrombocytopenia is known as one of the hematological abnormalities in about 45% of patients [32]. However, the role of AK in the platelet mitochondria is still unclear.